This invention relates to a permselective asymetric membrane suitable for hemofiltration comprised of a specific polyamide and to its use in the hemofiltration process and apparatus for carrying out hemofiltration.
Hemofiltration is a known process for detoxifying blood, i.e. for removing toxic metabolites, even those present in a low concentration, and excess water.
Metabolites are those components of the living cell, which control the normal course of metabolic reactions, as well as products of metabolism formed or catabolized in human or animal organisms, such as urea, proteins, carbohydrates, and electrolytes, e.g., sodium or potassium salts.
Asymmetric membranes normally have a total thickness ranging from 100 to 500 microns. Their structure is made up of a relatively thick, highly porous backing with an extremely thin skin of a thickness of 0.1 to 5 microns on the upper surface thereof. This skin is the actual permselective membrane, whereas the coarse, highly porous backing merely serves to support the skin and, in itself, has no selective properties, and does not offer any marked hydrodynamic resistance to the filtrate flow.
Polyamide-based membranes of this kind are known, and are used as desalting membranes for reverse-osmosis processes. In these dissolving-diffusing asymmetric membranes which are considered as having a compact skin, transport is effected through a dissolving process in the membrane, followed by a diffusion step. Separation, therefore, depends on the solubility in the membrane of the components of the solution to be treated. These polyamide membranes are described, for example, in German Offenlegungsschriften Nos. 19 41 022, 19 49 847, 23 08 197, 24 01 428, and 24 25 563. They are not suitable for hemofiltration, particularly on account of their molecular weight exclusion limits, their ultrafiltration capacities and the additives which are contained therein.
Contrary to the above-described membranes, membranes which are suitable for carrying out hemofiltration must be porous membranes, wherein the molecular weight exclusion limit of the membrane is determined by its pore-diameter. Only substances having molecules of a size smaller than the pore-size of a respective membrane are able to quantitatively pass through such a membrane. Up to the respective molecule size all metabolites, irrespective of their molecular weight, are thus completely removed in a similar ratio of concentration as in blood.
In hemofiltration an adjustable pressure-gradient serves as the driving force. Owing to a pressure-gradient existing at the membrane and to the resulting convective flow, toxic metabolites and excess water are faster eliminated from the blood and carried off than would be possible by means of the conventional hemodialysis. This convective flow, however, requires membranes which have a relatively stable pore-structure resembling continuous capillaries and are only slightly compressible when subjected to pressure. These stationary pores or capillaries offer a lower transport-resistance to convective flows than a gel-like homogenous pore-structure. Membranes having a stable pore-structure are also called macroporous or heteroporous membranes.
Conventional ultrafiltration membranes, on the other hand, as described in German Offenlegungsschrift No. 17 94 191 exhibit some of the properties which are valid for hemofiltration (e.g. molecular weight exclusion limit). However, an application for hemofiltration in a broad clinical range demands a spectrum of further preconditions.
Hemofiltration has various advantages over hemodialysis; for example, the time which is required for treatment of a person suffering from chronic kidney diseases is reduced, toxic metabolites are removed even if they are present only in minimal concentrations, and alleviation of specific symptoms, e.g., hypertension is achieved. However, the process has, nevertheless, not yet been generally accepted, since the membranes which are known so far do not comply with all requirements.
The mode of operation of hemofiltration makes great demands on the membranes, because, contrary to hemodialysis,, a pressure of up to about 0.9 bar is exerted upon the membrane. In order to ensure sufficient operational safety and easy insertion in the hemofiltration-apparatus, the membrane must have high flexibility and strength, even in the absence of an additional reinforcement which may be incorporated in the membrane or of a supporting backing. A reinforcement, as it is incorporated in conventional membrane materials, usually has the disadvantage that the effective membrane-surface is reduced and the occurrence of pin-holes is enhanced. A supporting backing, on the other hand, leads to a membrane which is too thick and inflexible. It must also be taken into account that any reinforcement or support of the membrane would cause additional expenses for material and would necessitate additional process-steps in the manufacture of the membrane. Due to requirements concerning the apparatus, therefore a self-supporting membrane is particularly advantageous. Furthermore, its wet-thickness in an aqueous solution and in blood, should be below 100 microns due to the particular condition in hemofiltration apparatuses. Only in this case an optimum blood-flow pattern and the necessary compactness of the apparatus are ensured in the hemofiltration apparatus. However, reduction of the wet-thickness to values below 100 microns leads to formation of microholes in most of the membranes, and in self-supporting membranes it will result in insufficient strength. Furthermore, this reduction usually has an adverse or at least unpredictable effect on the ultrafiltration-capacity and the molecular weight exclusion limit and other properties.
The ultrafiltration-capacity values and the molecular weight exclusion limit values of the membrane determined for water and for blood must be within particular limits, and the values obtained for blood should be comparable to those obtained for water. If the ultrafiltration-capacity for water is too low, or if it shows a marked drop when blood is used instead of water, this leads to the disadvantage that either an excessively large membrane surface must be employed for a sufficiently fast removal of water or the period of treatment has to be relatively long. If the ultrafiltration-capacity is too high, water is too quickly eliminated, which leads to problems regarding the supply of metabolites from cell-compartments and to symptoms of disequilibrium, and must be compensated for by expensive adjustment-procedures. Furthermore, the ultrafiltration-capacity is, within certain limits, related to the molecular weight exclusion limit.
The molecular weight exclusion limit should, if possible, be within a range wherein, on the one hand, even smaller macro-molecular metabolites can be removed and, on the other hand, the losses of larger vital proteins, particularly serum albumin, are kept low. For producing an optimum membrane, it is important that, for reasons of purity, the number of components is kept as low as possible and that the components are miscible with water and are, at least in traces, non-toxic. Furthermore, this would substantially facilitate the manufacturing process.
As far as possible the membrane must be free from toxic residues, or it must be possible to eliminate any toxic residues in a simple manner, without thereby causing a marked physical or chemical modification of the membrane. In particular, it must be possible to quantitatively remove the solvents, precipitating agents and purifying agents which are used in the manufacture of the membrane.
Another requirement which must be met by the membrane-forming polymer is a relatively low absorption of water; a slightly hydrated polymer forms the stable pore-structure resembling continuous stationary capillaries which is needed in the membrane. Only in this case can the dry membrane easily be handled when it is processed and inserted into the respective hemofiltration apparatus, and any compression or modification of the membrane under hemofiltration conditions is diminished.
A polymer of this kind would be particularly advantageous for the maufacture of non-shrinking membranes which may be stored in the dry state and which may be easily inserted as hemofilters into a hemofiltration apparatus and may be sterilized in the dry state.
A membrane which is optimally suitable for hemofiltration must, therefore, exhibit a high degree of flexibility and strength in the dry and in the wet state in order that it can be safely processed and inserted into the hemofiltration apparatus and also in order to guarantee operational safety. Furthermore, a membrane made of a thermoplastic material would have the advantage of being weldable, which could result in a simpler processing. Above all, a membrane of this kind must be free of pin-holes, it must readily be producible in a continuous manufacture on a commercial scale, and it must be easily processable in order that hemofiltration can be clinically used.
None of the membranes hitherto known has all of these favorable properties.
For example, cellulose acetate (see, e.g., NTIS Report PB-22 50 69) or polyacrylonitrile (German Auslegeschrift No. 21 45 183), when used as base materials of membranes for the "artificial kidney", exhibit an undesirably high absorption of water and the disadvantage connected therewith. They require, e.g., a very high content of plasticizers, in order to be storable in the dry state, and, in particular, they have poor handling properties and a low mechanical strength. Although membranes made of a polysulfone (German Auslegeschrift No. 22 28 537) or an aromatic polyamide or polyimide (German Auslegeschrift No. 23 42 072) or of cellulose triacetate ("Biotechnische Umschau" 1 (9), 280 1977) show a reduced absorption of water, they nevertheless present problems regarding reproducibility, handling properties, flexibility, resistance to tear-propagation, elongation, and pin-holes, particularly in the dry state at membrane-thicknesses below 100 microns. Furthermore, the conventional membranes are often manufactured using additives which can be removed only with difficulty. In total, these problems hamper an economic production of hemofiltration apparatus, especially in the case of flat sheet membranes. Finally, membranes made of the above-mentioned polymers show an undesired affinity for blood-constituents and a high absorption of proteins, whereby permeation properties and blood-compatibility are impaired.